Self-assembly pathways of E22Delta-type amyloid beta peptide mutants generated from non-aggregative O-acyl isopeptide precursors.

摘要

The recently identified E22Delta-type amyloid beta peptide (Abeta) mutants are reported to favor oligomerization over fibrillization and to exhibit more-potent synaptotoxicity than does wild-type (WT) Abeta. Abeta(E22Delta) mutants can thus be expected to serve as tools for clarifying the impact of Abeta oligomers in Alzheimer's disease (or Alzheimer's-type dementia). However, the biochemical and biophysical properties of Abeta(E22Delta) have not been conclusively determined. Here, we evaluated the self-assembly pathways of Abeta(E22Delta) mutants generated from water-soluble, non-aggregative O-acyl isopeptide precursors. Circular dichroism spectroscopy, Western blot analysis, and thioflavin-T fluorescence intensity and cellular toxicity assays suggest that the self-assembly pathways of Abeta(E22Delta) differed from those of Abeta(WT). Abeta1-40(E22Delta) underwent a rapid random coil-->beta-sheet conformational change in its monomeric or low-molecular-weight oligomeric states, whereas Abeta1-40(WT) self-assembled gradually without losing its propensity to form random coil structures. The Abeta1-42(E22Delta) monomer formed beta-sheet-rich oligomers more rapidly than did Abeta1-42(WT). Additionally, the Abeta1-42(E22Delta) oligomers appear to differ from Abeta1-42(WT) oligomers in size, shape, or both. These results should provide new insights into the functions of Abeta(E22Delta) mutants.